RNA catalysts and the origin of life

Conversation
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Since @John_Harshman wasn’t talking about an RNA at the origin of life, for the simple reason that RNAs at the origin of life wouldn’t necessarily have coded proteins, you’ll need to find a different (valid) example.

You seem to be under the misapprehension that protein coding had to exist from the beginning of life. That’s one of the main features of RNA world hypotheses - that no protein coding is needed. If protein coding was a later addition, and the available evidence suggests it was, your arguments[1] evaporate.

You also seem to think Brenner was talking about the origin of life. Having read his article, I don’t think he was.

  1. If I’ve understood them correctly, which may not be the case. ↩︎

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This
might be of interest.

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I’m going to call BS on that.

First of all because if DNA can “carry the information to encode a protein” then so can RNA, because the only way DNA can do that is by having a coding region.

But DNA is not an enzyme, it doesn’t translate or transcribe itself etc. So the only thing that could have been meant by the idea that RNA can “carry the information to encode protein like DNA” is for it to literally only contain a coding region. Nobody is suggesting the RNA molecule itself somehow actively transcribes and translates itself anymore than anyone is suggesting DNA does these things (and nobody is suggesting DNA itself can do these things.)

There is just no contemporary hypothesis for the origin of life that says any single RNA molecule could simultaneously carry out all the different functions of translation, and there is no-one suggesting DNA can do it either.

The only possible interpretation of the statement is that RNA is suggested to be able to carry coding regions that can be translated if the correct translation factors are present. That is after all what happens to DNA too, it is first transcribed into mRNA (by RNA polymerase enzymes made of protein), and these mRNAs are subsequently translated. Heck, if anything that seems to imply the DNA is actually superfluous to the capacity to contain coding region, as it is the mRNA that is translated and the DNA is merely transcribed.

If RNA can’t be considered “coding” because it doesn’t actively translate itself, then neither can DNA be considered coding because it ALSO doesn’t translate itself. So the phrase you keep quoting someone as having said, e.g. “just like DNA does” simply doesn’t make sense as anything other than the capacity of RNA and DNA to contain coding regions. Nobody is claiming such a statement entails the capacity of the very same molecule containing the coding region to self-translate, neither for DNA nor RNA.

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Also, frequently the capacity for DNA to “carry information” is understood merely as it’s ability to be replicated through templated replication (carry sequence information through multiple rounds of replication.)
In this way DNA is often contrasted with protein as DNA being information “storage” that carries the information that is replicated (the sequence-information is replicated) but is unable to act as enzymes and carry out the catalysis of chemical reactions etc., with proteins being the molecules that acts as enzyme and carry out functions, but cannot carry sequence-information and get replicated through complementary base-pairing (can’t serve as a template for it’s own replication).

But it is clear RNA can actually do both of these jobs, serve as a template for it’s own replication, while also being able to act as catalysts that carry out functions (ribozymes rather than enzymes).

So it’s just doubly confused to think a statement that:

Next you’ll be telling me that at the origin of life, “RNA can carry information just like DNA and be a catalyst at the same time!!”

-Is meant to imply that a putative self-replicating RNA ribozyme is also a molecule capable of translating itself, since nobody thinks DNA is able to do that either.

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Current research programs (and common sense) suggest that DNA segments can catalyse reactions. It just hasn’t been seen to do so naturally.

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If I can make a general comment without diving off the deep end into a discussion of dynamic systems - The origin of life is a change of state event, where a system transforms from precursor state properties to a new state and new properties. The precursor system wasn’t just (precursor) RNA, but also the environment containing and interacting with that RNA (notably metals and minerals). Just how that happened is a fair question, but I don’t think anyone claims RNA alone jump-started to life.

But the claim here is essentially that a starter motor without the car can never start the car. Taking RNA out of it’s environment and claiming it can’t be a functional part of life seems to commit several fallacies (I couldn’t decide on one).

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Is there even a claim here? Can you point to a clear statement of that claim?

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I am inferring a claim based on references to computability, control theory, and “threshold of complication”. A bit of googling lead me to discussions of homeostasis in cells. It’s certainly true that a single RNA can’t contains all of the information needed to control it’s environment (the cell), but who claims that it can?

If appsandorgs wanted to be more clear about this, he easily could. 15 years is plenty of time to write down a clear case with supporting references. Instead we get obfuscation, then a declaration of victory followed by a smug retreat. This is no better than claims of the improbability of evolution by people who are incapable of showing their work.

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Checking back in … I hope all had a good weekend. I apologize upfront for the lengthy post, all my comments have to be approved before being displayed, so I might as well make them at once.

This thread is about the supposed self-replicating RNA ribozyme at the origin of life. This subject is stated in the title of the thread. My comment (which set off this thread) explicitly mentions the origin of life. The opening comment in the thread correctly refers to the context of the origin of life. The second comment in the thread specifically explains the core position being discussed, which is, statements being made to the public/press about RNA at the origin of life. The next comment continues to reference the context of the origin of life — at which point, John Harshman basically suggested the topic be moved to this stand-alone thread. In his first comment after the move, he said “All an RNA needs to be coding is start with AUG and not have a stop codon too soon. I see no reason why there couldn’t be a ribozyme with those characteristics.” This comment appeared directly after I mentioned that the self-replicating RNA ribozyme “often envisioned at the origin of life” doesn’t establish the constraints needed to specify genetic information like DNA.

After reading his comment, I blinked my eyes a couple of times and thought he must have just rattled that off without thinking about it. So, giving him his due and using the least number of words possible, I merely suggested that he “re-read my comments for context”.

After that, he did nothing whatsoever to modify his comment, responding instead with a modest amount of snark — suggesting the dubious notion that my claim “a self-replicating RNA (at the origin of life) does not carry information like DNA” is a statement just too difficult to understand. So, after several rounds, I finally asked him point blank if his comment was correct. 5,600 words appeared on this forum between the time he made his comment and the time he acknowledged that his comment was incorrect in the context of this conversation (where it was made).

I ask you, honestly, if you were an average non-specialist person in the public, would you not have concluded that the self-replicating RNA envisioned at the origin of life can carry information like DNA? After all, an expert just told you it could.

If you did conclude that, then you would have been misled. DNA conveys information by virtue of codons. Codons are a system parameter imposed by the constraints working within the system. You can then ask, what is required to have a set of constraints impose a triplet reading-frame code on a sequence of DNA? To answer that question, the problems are compounded by orders of magnitude, and no one on the surface of this planet has any idea how to do it. You basically (to a very significant degree) have to solve the OoL problem to answer that question. That little detail might be a wee bit too important to leave out of the standard OoL proclamation “a self-replicating RNA can carry information just like DNA” —or— “all it needs is a start codon”. It is mis-leading and demonstrably false.

In short, what you suggested did not happen, occurred right in front of your very eyes. I realize that not a word I am saying will mean one wit to you, but that is your problem, not mine. If you want to know more, I suggest you start reading — it’s all well-documented in the literature. The key observations are not even controversial.

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The living cell has to specify itself among alternatives. It uses a system of tokens and constraints to covey this specification. Constraint is a word used to describe aminoacyl-tRNA synthetases by physicists and theoretical biologists who study the gene system. They often refer to these enzymes as a type of “non-holonomic” or “non-integrable” constraint — in the sense that the system has enough degrees of freedom to attach any number of different amino acids to the 3’-CCA end of a tRNA, but can constrain (control) that to just a single amino acid result. Doing so does not physically eliminate the degrees of freedom within the system, and it can immediately produce (control) a different result. This is a system requirement to read a sequence of bases, and produce a controlled response from it.

Here is what I said at the very top of this thread:

Any particular codon of DNA specifies just one of twenty alternative amino acids to be appended to a growing polypeptide during protein synthesis (with stop codons as well). Which one of the twenty alternative amino acids to be presented (for binding) is physically established by the genetic descriptions of a set of twenty molecular constraints. This means that the information that the system acquires from a codon of DNA (i.e. which amino acid it specifies in the genetic code) requires the simultaneous coordination of twenty sequences of genetic memory. This necessary state of coordination (variously described as closure or self-reference) was predicted to exist in 1948 and its molecular implementation was predicted in 1955, which was then confirmed via experiment in 1956-58.

Here is what John Harshman’s link says:

Aminoacyl-tRNA synthetases (aaRSs) implement the correct assignment of amino acids to their codons and are thus inherently connected to the emergence of genetic coding. These enzymes link tRNA molecules with their amino acid cargo and are consequently vital for protein biosynthesis.

The minimization of errors represents the utmost barrier for the development of biological complexity and accurate specification of aaRS binding sites is proposed to be one of the major determinants for the closure of the genetic code.

And here is what John Harshman says:

I certainly don’t know what you were trying to say … I don’t understand what the question means … I have no idea what you meant … I’m still curious about just what it is he’s trying to say … what in the heck are you talking about … I have no idea what you think you’re saying

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That is the second or third time you’ve made that type of comment about me, as a moderator. You seem so (so, so, so) very certain that I’ve committed some sort of trick or scam here and cannot wait ride off in “victory”.

I can’t express to you how wrong you are. There is absolutely no victory in this discussion. Not even a single member of this forum said anything resembling “Of course not … that would require a coding structure which comes from …”

As far as obfuscation, you can make your case by pointing out any false statements I’ve made about DNA, RNA, codons, aaRS, or the recorded history of discovery on this topic.

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Then mRNA conveys information by virtue of codons too. DNA doesn’t translate itself any more than RNA does.

Again, the informational capacity of DNA is usually referred to in terms of it’s capacity to transmit that information from generation to generation by acting as a template for complementary base-pairing, thus facilitating sequence-replication. Thus it conveys sequence-information down the generations.

Interestingly DNA is never actually translated, it’s sequence is only ever copied. It is when the sequence is transcribed into mRNA that the mRNA is translated. It is the anti-codons of tRNA that comes into contact with the codons of RNA.

Now, is there some overall point you wish to make about this? You seem scared to state explicitly what you want us to conclude about the relationship between RNA, DNA, protein, and the translation system. Just say it, we won’t bite that much.

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Just want to say that your summary contains a gross mischaracterization of everything I’ve said. Nor do I see what the “constraints”, by which you apparently mean the proteins that currently attach amino acids to tRNAs, have to do with the origin of life, given current ideas about the RNA world. You quote from a paper I cited but do not seem to understand what it says, even in the bit you quote-mine. You have described (in vague and nearly incomprehensible terms) the protein-synthesis system in extant life. But what conclusion do you draw about the origin of life from that? You won’t say.

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You have repeatedly made statements to the effect of “No one can prove me wrong” but refuse all requests to clarify what you mean. Obfuscation.

Yet you continue to claim victory.

I think a person with even minimal understanding would not assume that ALL necessary information for life is carried in a single RNA molecule. Your argument (AFAICD) depends on that RNA molecule being the sole carrier of information necessary for homeostasis. If I have misinterpreted what you mean, then it is on you to provide a better explanation.

Trifonov (2004) seems to have some idea how to do it. Maybe one of our biochemists can weigh in on this before the goalposts move?
Trifonov, E. N. (2004). The triplet code from first principles. Journal of Biomolecular structure and dynamics , 22 (1), 1-11.
'https://www.tandfonline.com/doi/abs/10.1080/07391102.2004.10506975

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On a related note the origin of life is commonly thought to have occurred basically gradually over a considerable period of time, and it isn’t really clear where exactly one would draw the line and say that “by now” in this period life has originated.

As such the origin of life is not so much a singular “event” or “instance” of extremely short duration, nor is it clear that a single self-replicating ribozyme should be considered a form of life all on it’s own. So it really doesn’t clarify or narrow down anything that you write about “the supposed self-replicating RNA ribozyme at the origin of life”, as the idea of a self-replicating RNA ribozyme in the context of the origin of life could still fit into a very broad range of hypotheses involving many different sorts of environments, structures, and macromolecules besides just putative self-replicator.

Incidentally, a self-replicator is also often thought to be a sort of universalist RNA replicase, capable of replicating many different RNA molecules in addition to itself (in the same way a DNA polymerase enzyme can polymerize basically any piece of single-stranded DNA given the right primer). So it is entirely conceivable that “the supposed self-replicating RNA ribozyme at the origin of life” fits into a context of numerous cooperating RNA molecules of which the replicator (able to replicate itself and others) is just one from among a larger evolving ensemble. As such there could entirely plausibly have been an RNA-based system in which a primitive translation system had already begun to take root, and that entire system is periodically replicated by the replicase ribozyme.

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Imo not a good paper for explaining why the code is based on triplets (it explains the order in which the codons evolved though).

Imo the best paper on the origin of the translation system (that also contains an explanation for why the code probably began in triplet form) this:

Did you know that the ribosome EVEN TODAY can catalyze polymerization of random peptides without mRNA being present? That is in complete absence of codon-anticodon interactions and tRNA translocation by the small ribosomal subunit? The large ribosomal subunit will accept, bind, and position aminoacylated tRNAs and catalyze multiple consecutive rounds of random peptide bond formation, making short random peptides.

The hypothesis is that initially mRNA evolved as a structural stabilizer that merely helped position and stabilize aminoacylated tRNA for more efficient peptidyl transfer. The small subunit then evolved (likely by exaptation from another function) to assist in translocation.

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All this talk about codons and very early protein evolution reminds me of a very interesting paper published in 2008, partly (it seems) in response to the claims by Axe that the protein universe is so vast as to be un-navigable by evolution. (The authors specifically cite Axe and end with a dismissal of ID.)

https://royalsocietypublishing.org/doi/10.1098/rsif.2008.0085

One thing they emphasize is the smaller early amino acid alphabet. Since they published the paper, I think we know a lot more about the stepwise development of that alphabet (see this paper from 2019):

This is of course several steps removed from an RNA World and from the OOL but I’m currently writing about the protein universe and how it relates to all of protein space (so I have active interest and lots of open tabs on this topic) and our interlocutor did start with the full-blown set of 20 amino acids (and no “degrees of freedom”–that still makes me laugh).

PS thanks to @Rumraket for a lot of great posts!

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I don’t personally see why we need to be bogged down on whether an RNA can carry a codon and be a catalyst at the same time. You can simply have different RNAs, each with different mutually helpful activities, inclosed together in a protocol. Or how about a population of protocols with some promiscuity in horizontal transfers between them.

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As a non-specialist[1] person in the public (albeit not average[2]) who did not conclude that, the answer is definitely “No”.

Incidentally, the second comment in this thread doesn’t include anything about statements to the public. You are confused.

Really? What system is that?

They don’t appear to be imposed by a system of RNA-based life, which appears to have originally existed without them, definitely existed without all of them, still exists without some of them, and may not have to exist at all.

Who says it has to be a triplet reading-frame code? tRNA molecules happen to link to triplets of mRNA strings, but I’m not aware of any reason why it has to be a triplet.[3] Alternatives have been proposed, including a 5-base twin reading-frame code with 25 tRNA-equivalents.

What I suggested did not happen was @John_Harshman talking about RNA at the origin of life. He has now said that you are misrepresenting him, suggesting it did not occur at all.

It’s not a problem for me at all. I’m used to blatherskites making false or unintelligible claims.

False claims like this one:

I don’t think this is true. Such terminology appears to be used by only one researcher (Howard Pattee) and those citing his work.

Here’s another false claim:

Any particular codon of DNA may specify different amino acids, depending on the organism/organelle which is producing the protein, from the 22 (not 20) amino-acids currently known to be added during protein synthesis, and may specify different things depending on the surrounding context.

For example, the TAG/UAG codon may append leucine, glutamic acid, glutamine, tryptophan, tyrosine or pyrrolysine, or act as a stop codon.

Because there are 64 possible triplets, there are more than 20 “molecular constraints” in any organism, even those that only use 20 amino-acids, because there are multiple different tRNA molecules that bind to some amino-acids.

Your view of protein synthesis does not take into account either variant or historical genetic codes. It is too simplistic.

See above.

Finally, I note that you didn’t respond to the rest of my post, which was about (i) the earliest life not using protein coding at all, and (ii) Brenner’s article. Ignoring rebuttals is a common technique among those who don’t know what they’re talking about.

  1. I’m a software engineer, not a biologist. ↩︎

  2. This is a science forum. No-one here is average. In fact, no-one anywhere is average - as the USAF discovered. But that aside, you should expect people on a science forum to have an above average knowledge of science[4] and tailor your posts to your audience. ↩︎

  3. Physical space requirements resulting from having to have two tRNAs side-by-side to ensure amino-acid linkage may result in such a constraint. Or may not. That’s beyond my pay grade. ↩︎

  4. Drive-by creationists excepted. ↩︎

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I study biology and have for decades. There’s nothing symbolic there. It’s all chemistry. It’s only symbolic in the ways that people use to discuss it.

Since there’s no symbolism, your going on about tokens and constraints makes no sense.

Neither fully specify the amino acid RESIDUES (the acid aspect is eliminated during protein synthesis) in FUNCTIONAL proteins. No intelligent designer would design what we actually observe, which is why IDcreationists ignore all of the posttranslational modifications added later. An intelligent designer would just use some of the redundancy in the genetic code to handle that.

I don’t. Moreover, there’s no evidence that you understand anything that you are quoting.

How about answering those questions? They should be easy, given your claims about what you have studied.

No, you have stated zero awareness of much of what is in the primary OOL literature.

You have demonstrated zero awareness of metabolism-first hypotheses.

I see zero awareness of actual study. I only see that you are parroting creationist straw men.

Again, studying “these specific issues” would require familiarity with the relevant primary literature.

To repeat:

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You would know better than I. Either one belies the statement, “… and no one on the surface of this planet has any idea how to do it.”

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This is something that I have also been thinking about. Whether there can be a ribozyme (X) capable of replicating itself by using another X as a template strand, which produces the complementary X’ which can be used as a template to make more X. The question I have is, why don’t we see this in biology or among viruses? If it was a stable state that preceded the current state of life where proteins do the job of template directed polymerization of RNA and DNA, then why doesn’t a ribozyme RNA/DNA polymerase exist anymore in some form or another in nature (or maybe it does, I am not aware)?

One could argue that proteins do the job more efficiently such that any old ribozyme was superseded and lost. That could be true, but that also raises the question for why we do still have a couple of very important ribozymes still remaining: Self-splicing introns, spliceosomes that likely evolved from self-splicing introns, RNAse-P that is involved in the maturation of tRNA, various others that can perform (self-) cleavage and/or ligation of RNA, and finally ribosome, which is also composed of proteins but the catalytic PTC site is entirely RNA and a ‘naked’ (protein free) ribosome is capable of peptide bond formation.

One side note: it’s a curious fact that, while prokaryotes only have one RNA polymerase, eukaryotes have multiple types of RNA polymerases that produces distinct classes of RNA. RNA Pol I transcribes rRNA except for 5S RNA, Pol II transcribes mRNA, and Pol III transcribes tRNA, 5S RNA, RNAse-P and spliceosomal RNA. I don’t know why this is he case.

So, ribozymes mostly perform cleavage/ligation on polynucleotides and mediate peptide bond formation, but none perform template directed nucleotide polymerization. If proteins are so much better catalysts such that they replaced these, why didn’t proteins replace the other ribozymes that we still have, such as the ribosome?

My guess (it’s a guess admittedly so I may be wrong) is that a ribozyme transcribing itself wouldn’t work. Let’s suppose there is a ribyzome X, which transcribes another X as a template strand, producing the complement X’ and that is transcribed to make more X. If there is any degree of error, this ribozyme would quickly destroy itself via a run-away feedback loop. One error could make the X ribozyme of the next generation more error prone, and producing more error prone X ribozymes, until any degree of fidelity (or the catalytic function itself) is lost and self-replication grinds to a halt. Why doesn’t this also happen with the protein based replication of RNA and DNA one might ask? After all, you can have the same feedback. Protein polymerases make an error in the coding strand for the polymerase itself, which makes the protein polymerase more error prone, producing more errors later. This doesn’t happen because (as I discussed in a previous comment) the translational system and the genetic code buffers against errors, and proteins themselves often tolerate errors (robustness). Again, take this with a grain of salt, I am open to hear any other suggestions or disagreements.